9-or 10-halo-4h-benzo{8 4,5{9 cyclo-hepta{8 1,2-b{9 thiophen-4-ones

ABSTRACT

The present invention concerns novel compounds of the formula,   WHEREIN R1 is hydrogen, halogen, or alkoxy of 1 to 4 carbon atoms, and Y is chlorine or bromine in the 9 or 10 position. The compounds are intermediates for the production of pharmacologically active compounds, particularly for compounds which are histaminolytics.

ilited States Patent [191 Bourquin et a1.

10-HALO-4H-BENZO[4,5]CYCLO-HEP- TA l ,2-B ]THlOPHEN-4-ONES [75]Inventors: Jean-Pierre Bourquin,

Magden/Aargaw; Gustav Schwarb, Allschwil; Erwin Waldvogel, Aesch, all ofSwitzerland [73] Assignee: Sandoz Ltd., Basle, Switzerland [22] Filed:Aug. 8, 1972 [21] Appl. No.: 278,738

Related US. Application Data [63] Continuation-impart of Ser. No.278,244, Aug. 7, 1972, Pat. No. 3,749,786, which is acontinuation-in-part of Ser. No. 120,738, March 3, 1971, Pat. No.3,682,930, and a continuation-in-part of Ser. No. 178,449, Sept. 7,1971, Pat. No. 3,770,728.

[30] Foreign Application Priority Data Mar. 11, 1970 Switzerland 3598/70July 31, 1970 Switzerland .l 11593/70 Sept. 24, 1970 Switzerland14120/70 Feb. 4, 1971 Switzerland 1632/71 [52] 11.8. CI. 260/332.3 P,424/267, 260/293.57, 260/268 TR,260/247.l [51] Int. Cl C07d 63/18 [58]Field of Search 260/332.3 P, 570.8 TC, 260/240 R [56] References CitedUNITED STATES PATENTS 3,491,103 1/1970 Jucker et a1. 260/293.4

[ Dec. 10, 1974 3,574,199 4/1971 Coyne et a1. 260/240 TC 3,632,8571/1972 Kyburz et Z11. 260/570.8 TC 3,709,947 1/1973 CuSic et a12150/5708 TC X 3,749,786 7/1973 Bourquin et a1. 424/267 FOREIGN PATENTSOR APPLICATIONS 246,130 4/1966 Austria 260/3323 Primary ExaminerJohn D.Randolph Attorney, Agent, or FirmGera1d D. Sharkin; Richard E. Vila v [57] ABSTRACT The'present invention concerns novel compounds of theformula,

\H/ wherein R is hydrogen, halogen, or alkoxy of l to 4 carbon atoms,and

Y is chlorine or bromine in the 9 or 10 position.

The compounds are intermediates for the production of pharmacologicallyactive compounds, particularly for compounds which are histaminolytics.

8 Claims, No Drawings 9-011 l-HALO-4H-BENZOl4,5]CYCLO-HEPTA[1,2- JTH O H-twherein R is hydrogen, halogen, or alkoxy of 1 m4 carbon atoms, and

Y is chlorine or bromine in the 9 or 10 position. The compounds offormula VII may, for example, be produced by chlorinating orbrominatinga compound of formula IX,

R1 Q Q \g/ wherein R is as defined above, to obtain the corresponding9,l0-dic hloroor 9,10-

dibromo compounds, and subsequently converting the resulting compoundsinto compounds of formula VII under alkaline conditions, e.g. byreaction with a solution of potassium hydroxide in an inert organicsolvent such as methanol, or, e.g., by heating with a commercialsolution or sodium or potassium hydroxide in the presence of a loweralcohol solvent.

The above 9,10-dibromo compounds obtained from the compounds of formulaIX may, for example, likewise be obtained by reacting a compound offormula X,

wherein R, is as defined above, .with the stoichiometric amount of .N-'

bromosuccinimide in an inert organic solvent, e'.g. a chlorinatedaliphatic hydrocarbon such as carbon tetrachloride.

The compounds of formula VII are useful intermediates for the productionof pharmaceuticals, for example, compounds of formula I,

AB S I in which R is as defined-above, 1 R is alkyl of l to 4 carbonatoms, and A-B- is the group CI-I CO- or COCI-I The compounds of formulaI may be prepared from compounds of formula VII by the followingsequence of reactions.

A compound of formula I is obtained by a process comprising a.hydrolyzing a compound of formula II,

wherein R and R are as defined above, and X is in the 9 or 10 positionand is an OR radical, wherein R is alkyl of l to 4 carbon atoms, aradical of formula III,

- v cum1 III wherein R is hydrogen or alkyl of l to 4 carbon atoms, and

R is hydrogen or alkyl of l to 4 carbon atoms which is unbranched on thea carbon atom, or

R and R together with the nitrogen atom, form asaturated 5-, or6-membered heterocyclic ring, the heterocycle being selected from thegroup of heterocycles containing 1 or 2 nitrogen atoms, 1 nitrogen atomand a further hetero atom selected from oxygen and sulphur, and 1nitrogen atom and one nitrogen atom substituted by an alkyl radical of lto 4 carbon atoms, or

b. alkylating a compound of formula IV,

wherein R is as-defined above,

wherein R and R are as defined above.

The resulting compound of formula I may be isolated in the forni of afree base or as an acid addition salt thereof.

Particularly suitable R, radicals are hydrogen, chlorine, bromine andmethoxy.

The symbol X in formula ll is suitably the tertbutoxy group, thedimethylamino, diethylamino or nbutylamino radical, and when X denotes aheterocycle, it may be, e.g., the piperidine, piperazino, morpholino,pyrrolidino or N-methyl-piperazino radical.

The term inert solvent as used herein signifies an organic solvent whichis inert under the reaction conditions.

The production of compounds of formula I in accordance with processvariant (a) may, for example, be effected by heating compounds offormula ll in an aqueous acid solution. The reaction temperature is notcriti-. cal. A suitable reaction temperature is approximately 50 to100C; the reaction is preferably effected at the reflux temperature ofthe reaction mixture.

Suitable acids are aqueous inorganic acids, e.g. 'hydrochloric,sulphuric or phosphoric acid, and aqueous organic acids, eg formic,acetic, fumaric or oxalic acid.

The hydrolysis may also be carried out by hydrolyzing a mixture ofcompounds of formula II substituted in the 9 position with correspondingcompounds of formula ll substituted in the 10 position. Suchhydrolysisresults in a mixture of isomers'of la and lb,

wherein R, and R are as defined above, and said isomers may be separatedin conventional manner, for example by'fractional crystallization of aalkyl halides, with esters of organic sulphonic acids, 6

eg methane-,benzeneor p-toluene-sulphonic acid, or with dialkylsulphates, in an inert solvent and in the presence of a basiccondensation agent.

The compounds of formula I may be isolated from the worked up reactionmixture in conventional manner, e.g. chromatographically.

The compounds of formula II are likewise new.

Compounds of formula Ila,

l R? mi s wherein I R and R are as defined above, and X is in the 9 or10 position and is a radical of formula III, may, for example, beobtained by reacting a compound of formula V, Y

wherein Y R and R are as defined above, and

Y is chlorine or bromine in the 9 or 10 position, or a mixture of acompound of formula V substituted in the 9 position, with a compound offormula V substituted in the 10 position, in the presence of anacid-binding agent, e.g. an alkali metal amide or. hydride or apotassium alcoholate, e.g. a potassium tertLbutylate, with thecorresponding amine or saturated, nitrogen-containing heterocycle.

This reaction yields a mixture of compounds of formula Ila substitutedin the 9 position, with compounds of formula [la substituted in the; 10position. A separation may be effected in accordance with known methods,but is not necessary; the worked up mixture is generally further workedup as such.

Compounds of formula llb,

preferably efiected at room temperature or at a slightly elevatedtemperature.

This reaction likewise yields a mixture of the compounds of formula llbsubstituted in the 9 position, with the compounds of formula lIbsubstituted in the 10 position, which mixture is generally notseparated, but further worked up after working up the reaction mixture.

The compounds of formula IV may, for example, be obtained bydealkylation of compounds of formula la in accordance with knownmethods. For example, compounds of formula Ia are treated with acyanogen halide, preferably cyanogen bromide, or a halogen formic acidester. In this reaction the radical R is first replaced by the cyano oralkoxycarbonyl group. The reaction is conveniently effected in an inertorganic solvent, e.g. an open chain or cyclic ether such as diethylether or tetrahydrofuran, an aromatic hydrocarbon such as benzene, achlorinated aliphatic hydrocarbon such as methylene chloride, and at areaction tempera ture between room temperature and the boilingtemperature of the reaction mixture. The cyano or alkoxycarbonyl groupis subsequently .split off in accordance with known methods, e.g. byacid hydrolysis.

The compounds of formula V, which are likewise new, may be obtained bydehydrating a compound of formula VI,

wherein R and Y are as defined above,

in an inert organic solvent, e.g. an open chain or cyclic ether such astetrahydrofuran or diethyl ether, to a magnesium organic halogencompound of formula VIII,

wherein I by dehydration.

- bromic acid, strong organic acids, such as acetic anhy- R is asdefined above, and

Hal signifies chlorine, bromine or iodine, in the same inert solvent inwhich it was prepared, conveniently stirring the reaction mixture forabout I k hours, preferably at room temperature, and subsequentlyhydrolyzing. Hydrolysis may, for example, be effected with an aqueousammonium chlorine solution in the cold. The compounds of formula VII mayalso be used for 10 the production of intermediates useful in aparticularly efficient process for the production of compounds offormula la described above. The compound of formula VII is reacted withan organic magnesium compound of formula- XI,

RrO-MgHal Hal is chlorine, bromine or iodine, and

R is as defined above, and the reaction product is hydrolyzed to yielda-compound of formula XII,

20 in which p YU in which R R and Y are as defined above.

The compound of formula XII may be converted into into compounds offormula XIII,

' =I=v I d v XIII in which R,, R and Y are as defined above,

Examples of water-removing agents which may be used for the dehydrationare: mineral acids such as sulphuric acid, ethanolic hydrochloric acidor hydrodride, or inorganic acid halides.

The compounds of formula XIII may be converted into compounds of formulaIa by treatment with a strong, aqueous non-oxidising acid. Suitablestrong acids for the reaction are inorganic acids, e.g. sulphuric,hydrochloric,- hydrobromicand phosphoric acids, and strong organicacids, e.g. aliphatic and aromatic sulphonic acids, e.g.methanesulphonic and toluenesulphonic acids and trifluoroacetic andtrichloroacetic acids.

Certain acids, notably nitric acid, cause oxidation of the compounds,resulting in carbonisation or charring cent aqueous strong acid, toabout 80 to 120C.

The reaction period may range between 1 and about hours, depending onthe type and concentration of the acid used, and the reactiontemperature.

When an extremely dilute acid or a slightly weaker acid, such as onewhich gives a reaction mixture having a pH of up to 3, is used, thereaction is conveniently effected at an elevated temperature, e.g. atabout 200 to 230C, and under pressure.

The compounds of formula ll are fairly or readily soluble in aqueousacids. Therefore, the addition of asolution acid is generally notessential. When a solution aid, e.g. an alkanol, is used, then it isadvisable to keep the percentage of this solution aid as low aspossible.

When an appropriate water-removal agent, i.e. a

strong, aqueous, non-oxidising acid, is used, the compounds of formulaXll may be converted into the compounds of formula la without isolationof the compounds of formula Xlll. in this direct process variant it isadvisable to keep the percentage of any solution aid used as low aspossible.

The compounds of formula VI] may, for example, be produced bychlorinating or brominating a compound resulting compounds intocompounds of formula Vll under alkaline conditions, e.g. by reactionwith a solution of potassium hydroxide in an inert organic solvent suchas methanol, or, e.g., by heating with a commercial solution or sodiumor potassium hydroxide in the presence of a lower alcohol solvent.

The above 9,10-dibromo compounds obtained from the compounds of formulalX may, for example likewise be obtained by reacting a compound offormula X,

R1 "*0 Y; i,

wherein R, is as defined above, with the stoichiometric amount 1 of N-bromosuccinimide in an inert ogranic solvent, e.g. a chlorinatedaliphatic hydrocarbon such as carbon tetrachloride; I I

Insofar as the production of the starting materials is not described,the compounds are known or may be produced in accordance with knownprocesses or in a manner analogous to the processes described herein orto known processes. I y

The compounds of formula I and pharmaceutically acceptable acid additionsalts thereof are useful because they possess pharmacological activityin anmials. More particularly,- compounds of formula la are useful asspecific histaminolytics, and the compounds of formula lb, on the otherhand, the useful antaminics, i.e. they are useful in antagonizing theeffects of each of the biogenic amines. histamine, serotonin andacetylcholine.

For use of a compound of formula la as a specific histaminolytic or acompound of formula lb as an antaminic, the dose to be administered willnaturally vary depending on the compound employed, the mode ofadministration and the treatment desired. However, the

doses are similar for compounds of formula la and compoundsof formulalb, and satisfactory results for each group of compounds are obtained atdoses between about 0.004 mg/kg and 0.15 mg/kg animal'body weight. Forthe larger mammals, the daily dose'is from about 0.25 to about 10milligrams of. the compound, which maybe administered in divided doses2to 3 times a day or in sustained release form. Unit dosage formssuitable for oral administration incorporate from about 0.1 to about 5milligrams of the compound, in association with a pharmaceutical carrieror diluent.

In the following non-limitative Examples all temperatures are indicatedindegrees Centigrade.

EXAMPLE 1 '9 l0)-Bromo-4H-benzo[4,5 ]cyclohepta[ 1,2-

b]thiophen-4-one A mixture of g of9,l0-dibromo-9,l0-dihydro-4l-lbenzo[4,5]cyclohepta[ l,2-b]thiophen-4-one, 3 1.6 g of potassium hydroxide and 3,200 cc ofmethanol is heated under reflux while stirring for 2 hours. The mixtureis subsequently stirred at 0-5 for approximately 4 hours, and thecrystalline product is filtered off. After recrystallizing from al00-fold quantity of methanol, pure 9, l 0-bromo-4l-l-benzo[4,5]cyclohepta[ 1 ,2- blthiophen-4-one, having a M.P. of l34l35, isobtained. -Microanalysis agrees with the formula C, H BrOS. lnaccordance with the nuclear magnetic resonance spectrum the bromine atomis in the 9 or 10 position (probably in the 10 position).

The starting material was obtained as follows:

A mixture of l29 g of 9,l0-dihydro-4H-benzo[4,5]- cyclohepta[l,2-b]thiophen-4-one, 214 g of N- bromosuccinimide, 1.2 g of benzolyperoxide and 2,000 cc of absolute carbon tetrachloride is boiled underreflux while stirring for 3 hours. The mixture is subsequently filteredwhilst hot and the filtrate is concentrated to one third of its originalvolume. After allowing to stand at room temperature for several hours,the crystalline product is filtered, off and dried. This crude productis recrystallized from a 7-fold quantity of chloroform. Pure9,l0-dibromo-9,l0-dihydro-4H- benzo[4,5 ]cyclohepta[l,2-b1thiophen-4-one, having a M.P. of l34l35 (decomp.), is obtained inthis manner. Microanalysis agrees with the formula C H Br OS. Thestructure was ascertained with the nuclear magnetic resonance spectrum.

EXAMPLE 2 9( lO)-Bromo-6-chloro-4H-benzo{4,5 ]cycloheptal,2-bl-thiophen-4-one A mixture of 28.5 g of 6-chloro-9,l0-dibromo-9,l0-dihydro-4-H-benzo[4,5 ]cyclohepta[ l,2-b]thiophen- 4-one, 320 cc ofmethanol and 11.8 g of potassium hydroxide is boiled at reflux for 1hour. The reaction mixture is subsequently cooled, 320 cc of water areadded, and the crystals are filtered off. The crystalline product iswashed with a large quantity of water and dried in a vacuum at 60.Recrystallization is subsequently effected from a 20-fold quantity oftetrahydrofuran. Pure 9( 10)-bromo-6-chloro-4H-benzo-[4,5]cyclohepta[1,2- b]thiophen-4-one, having a M.P. of 198200, is obtained in thismanner. Microanalysis agrees with the formula C l-l BrClOS. Thestructure was ascertained with the nuclear magnetic resonance and massspectrograph spectra.

The starting material was obtained as follows:

A mixture of 26 g of 6-chloro-9,lO-dihyro-4H-benzo-[4,5]cycloheptal[1,2-b]thiophen-4-one, 260 cc of absolute carbontetrachloride, 39 g of N-bromosuccinimide and 0.5 g of dibenzolyperoxide is heated at reflux for 4% hours. The suspension issubsequently cooled and allowed to crystallize over night at 5. Thecrystalline product is filtered off and suspended in 65 cc of absoluteethanol. The crystalline product is subsequently filtered off and washedwith a large quantity of water. After drying at 60 in a vacuumrecrystallization is effected from a 20-fold quantity ofchloroform/petroleum ether (1:1). Pure 6-chloro-9,10-dibromo-9,l()-dihydro-4l-l-benzo[4,5]cyclohepta[1,2-b]thiophen- 4-one, having adecomposition point of l47149, is obtained in this manner. Microanalysisagrees with the formula C l-l Br ClOS.

EXAMPLE 3 9( 10)-Bromo-7-chloro-4H-benzo[4,5]cyclohepta[ 1,2-b]-thiophen-4-one The title compound was obtained in analogous manner tothat of Example 1, M.P. 218220.

EXAMPLE 4 6,9( l0)-Dibromo-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4-oneThe title compound was obtained in analogous manner to that of Example1, M.P. l77190.

EXAMPLE 5 9( 10)-Bromo-7-methoxy-4H- benzo[4,5 ]cyclohepta[l,2-b]-thiophen-4-one The title compound was obtained in analogousmanner to that of Example 1, M.P. 182-184.

EXAMPLE 6 9( 10)-Bromo-6-chloro-4H-bcnzo[4,5 ]cyclohepta[ 1 ,2-b]-thiophen-4-one The title compound was obtained in analogous manner tothat of Example 1, M.P. l98200.

EXAMPLE- 7 9(lO)-Chloro-4H-benzo[4,5]cyclohepta[1,2- b]thiophen-4-one Inanalogous manner to Example 1, but using chlorine gas and usingchclohexane as solvent, the title compound is obtained, M.P. 124126.

What is claimed is:

1. A compound of the formula:

R1 L I in which R is hydrogen, halogen or alkoxy of 1 to 4 carbon atoms,and

8. The compound of claim 1 which is 9(10)-chloro-4H-benzo[4,5]cyclohepta[1,2]thiophen-4-one.

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is9(10)-bromo-4H-benzo(4, 5)cyclohepta(1,2-b)thiophen-4-one.
 3. Thecompound of claim 1 which is9(10)-bromo-6-chloro-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-one. 4.The compound of claim 1 which is9(10)-bromo-7-chloro-4H-benzo(4,5)cyclohepta(12,-b)thiophen-4-one. 5.The compound of claim 1 which is 6,9(10)-dibromo-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-one.
 6. The compound of claim 1 which is9(10)-bromo-7-methoxy-4H-benzo(4,5)cyclohepta(1,2-b)thiophen-4-one. 7.The compound of claim 1 which is9(10)-bromo-6-chloro-4H-benzo(4,5)cyclohepta(1,2)thiophen-4-one.
 8. Thecompound of claim 1 which is 9(10)-chloro-4H-benzo(4,5)cyclohepta(1,2)thiophen-4-one.